In the last 10 years, orthotopic organ transplant has become an irreplaceable therapeutic method for patients having particular, terminal stage organ diseases, such as for example hepatic, cardiac, pancreatic, pulmonary and renal diseases.
However, rejection of the transplanted organ continues to be a substantial problem.
For example, rejection contributes to a mortality rate of 15-25% during the first year after surgery in the case of liver transplantation (Strasberg S. M. et al., Hepatology 1994, 20: 829).
The phases in which the liver for transplantation undergo damage have been determined as:
1) Heat ischemia during the removal from the donor;
2) Cold ischemia during the hypothermic storage phase;
3) Reperfusion of the organ in the recipient;
(Transplantation 53:957-978, 1992).
The basic strategy for the storage of organs for transplantation is that of slowing down the cellular catabolic processes through lowering the temperature of the organ from 37° C. to around 4-6° C. (hypothermia).
Hypothermia lowers the metabolic rate and the rate of hydrolysis catalysed by various intracellular enzymes, but does not completely inhibit cellular metabolism. This can bring about processes which lead to cellular alterations both in the endothelial sinusoidal compartment and in the hepatocytic compartment.
In fact, cooling of the isolated liver without perfusion results in a rapid reduction in ATP and ADP levels (J. Surg. Res. 23:339-347, 1977; Cryobiology 31:441-452, 1994) in as much as the residual energy demands exceed the cellular capacity to generate ATP through anaerobic glycolysis from glycogen reserves, with the consequent accumulation of lactic acid and intracellular acidosis.
The degradation of ATP to ADP and successively to AMP and adenine causes, during hypothermia, an accumulation of hypoxanthine with the concomitant conversion of xanthine dehydrogenase to xanthine oxidase, and is associated with increases in intracellular calcium and protease activation (McCord J. M., N. Engl. J. Med. 1985, 312: 158).
In the reperfusion state, this results in degradation of hypoxanthine to xanthine and then to uric acid with the production of reactive oxygen intermediates (ROI) and oxidative type damage.
Furthermore, the diminished activity of enzymes, such as, for example, the Na/K ATPases results in changes in the conditions of electrolyte balance with consequent water influx and cellular swelling.
In recent years, a direct correlation between ATP content during hypothermic storage of the organ for transplantation, and the success of the transplant in humans has been demonstrated (Hepatology 1988, 8: 471).
To overcome such disadvantages, storage solutions whose composition has been studied to counteract the dangerous effects of anoxic hypothermia (during the storage phase) and of the normothermic reperfusion (during re-implantation phase) are used.
The formulation of such solutions is in continuous evolution to allow the improvement of the vital state of the organ and the increase of preservation times.
Solutions useful for the storage of organs awaiting transplantation are already known.
In Transplantation 2000 Apr. 15; 69(7):1261-5) it is reported that the solution from the University of Wisconsin, known as UW solution, is capable of retarding the catabolic processes and guaranteeing good preservation of the organs awaiting transplantation.
The composition of UW solution is based upon a pharmacological strategy, which intends to:    1) favour the re-synthesis of ATP through the addition of precursors such as adenine and phosphate;    2) prevent acidosis through the presence of phosphate buffer;    3) inhibit xanthine oxidase activity through allopurinol;    4) minimise the ionic redistribution using a composition similar to that found intracellularly (high K+); and above all    5) prevent cellular swelling through osmotic pressure, through the addition of lactobionate, raffinose and high molecular weight colloids, such as starch.
The basic strategy of this composition is however empirical, and it has been hypothesised that the effect could derive from a phenomenon known as “sum of protections” (Southard J. H. et al., Transplantation 1990, 49: 251).
In Transplant Proc. 1999; August; 31(5):2069-70 it is reported that the Celsior solution is useful for the storage of organs awaiting transplantation.
The saline solution EuroCollins is another known solution, useful for the storage of organs, having the composition reported in the following Table 1.
TABLE 1ConcentrationK2HPO4•3H2O32mMKH2PO415mMKCl15mMNaHCO310mMGlucose194mM
This solution has been considered for many years the standard solution in Europe for the storage of organs, in particular kidneys. Its formulation is based on obtaining an electrolytic composition which simulates the intracellular environment. Further, in this solution, hypertonicity (420 mOsmol) is obtained by the addition of high glucose concentrations (around 190 mM).
The above-cited solutions are not without inconveniences, and have been subject to numerous modifications.
The principal disadvantages shown by UW solution lie in its high viscosity, with consequent possible damage, above all sustained by the endothelial cells, during perfusion of the organ, and in the high cost of each single component whilst remaining unsure as to their indispensability [Transplant Proc. 1999; August; 31(5):2069-70.
Celsior solution presents the disadvantage of not being a suitable solution for liver storage, if compared to solution UW [Transplant. 2000; Oct. 27; 70(8):1140-2].
EuroCollins solution presents numerous disadvantages:    1—has a high glucose concentration which aggravates the problem of acidosis, due to the enormous production of lactate during hypothermic hypoxia;    2—does not prevent cellular swelling during the storage of the organ;    3—is no better than solution UW (Transplantation 2000 Apr. 15; 69(7):1261-5).
The use of carnitines in the medical field is already known.
In Ann. Thorac. Surg. 2001; 71:254-9 the use of L-carnitine for the treatment of cardioplegic ischemia, in isolated rabbit heart is described. This work reports that L-carnitine shows a protective effect on the recovery of cardiac functions in isolated rabbit heart, when this was perfused with whole blood in to which L-carnitine had been added.